Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer

Mary Ellen Taplin, Meredith M. Regan, Yoo Joung Ko, Glenn J. Bubley, Stephen E. Duggan, Lillian Werner, Tomasz (Tom) Beer, Christopher Ryan, Paul Mathew, Shi Ming Tu, Samuel R. Denmeade, William K. Oh, Oliver Sartor, Christos S. Mantzoros, Roger Rittmaster, Philip W. Kantoff, Steven P. Balk

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    Abstract

    Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5α-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). Results: Prostate-specific antigen response rate (≥50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. Conclusion: The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation.

    Original languageEnglish (US)
    Pages (from-to)7099-7105
    Number of pages7
    JournalClinical Cancer Research
    Volume15
    Issue number22
    DOIs
    StatePublished - Nov 15 2009

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    Ketoconazole
    Castration
    Androgens
    Hydrocortisone
    Prostatic Neoplasms
    Dehydroepiandrosterone Sulfate
    Androstenedione
    Dihydrotestosterone
    Testosterone
    Therapeutics
    Prostate-Specific Antigen
    Oxidoreductases
    Thrombosis
    Research Design
    Dutasteride
    Hormones
    Confidence Intervals
    Recurrence

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. / Taplin, Mary Ellen; Regan, Meredith M.; Ko, Yoo Joung; Bubley, Glenn J.; Duggan, Stephen E.; Werner, Lillian; Beer, Tomasz (Tom); Ryan, Christopher; Mathew, Paul; Tu, Shi Ming; Denmeade, Samuel R.; Oh, William K.; Sartor, Oliver; Mantzoros, Christos S.; Rittmaster, Roger; Kantoff, Philip W.; Balk, Steven P.

    In: Clinical Cancer Research, Vol. 15, No. 22, 15.11.2009, p. 7099-7105.

    Research output: Contribution to journalArticle

    Taplin, ME, Regan, MM, Ko, YJ, Bubley, GJ, Duggan, SE, Werner, L, Beer, TT, Ryan, C, Mathew, P, Tu, SM, Denmeade, SR, Oh, WK, Sartor, O, Mantzoros, CS, Rittmaster, R, Kantoff, PW & Balk, SP 2009, 'Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer', Clinical Cancer Research, vol. 15, no. 22, pp. 7099-7105. https://doi.org/10.1158/1078-0432.CCR-09-1722
    Taplin, Mary Ellen ; Regan, Meredith M. ; Ko, Yoo Joung ; Bubley, Glenn J. ; Duggan, Stephen E. ; Werner, Lillian ; Beer, Tomasz (Tom) ; Ryan, Christopher ; Mathew, Paul ; Tu, Shi Ming ; Denmeade, Samuel R. ; Oh, William K. ; Sartor, Oliver ; Mantzoros, Christos S. ; Rittmaster, Roger ; Kantoff, Philip W. ; Balk, Steven P. / Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 22. pp. 7099-7105.
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    abstract = "Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5α-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). Results: Prostate-specific antigen response rate (≥50{\%} decline) was 56{\%} (32 of 57; 95{\%} confidence interval, 42.4-69.3{\%}); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30{\%}) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32{\%} with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89{\%}, androstenedione by 56{\%}, and testosterone by 66{\%}, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. Conclusion: The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation.",
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    AU - Taplin, Mary Ellen

    AU - Regan, Meredith M.

    AU - Ko, Yoo Joung

    AU - Bubley, Glenn J.

    AU - Duggan, Stephen E.

    AU - Werner, Lillian

    AU - Beer, Tomasz (Tom)

    AU - Ryan, Christopher

    AU - Mathew, Paul

    AU - Tu, Shi Ming

    AU - Denmeade, Samuel R.

    AU - Oh, William K.

    AU - Sartor, Oliver

    AU - Mantzoros, Christos S.

    AU - Rittmaster, Roger

    AU - Kantoff, Philip W.

    AU - Balk, Steven P.

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    N2 - Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5α-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). Results: Prostate-specific antigen response rate (≥50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. Conclusion: The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation.

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